Coordinated gene expression is required for phenotypic switching between epithelial and mesenchymal phenotypes during normal development and in disease states. Trophoblast stem (TS) cells undergo epithelial-mesenchymal transition (EMT) during implantation and placentation. Mechanisms coordinating gene expression during these processes are poorly understood. We have previously demonstrated that MAP3K4-regulated chromatin modifiers CBP and HDAC6 each regulate thousands of genes during EMT in TS cells. Here we show that CBP and HDAC6 coordinate expression of only 183 genes predicted to be critical regulators of phenotypic switching. The highest-ranking co-regulated gene is the NF-κB family member Rel. Although NF-κB is primarily regulated post-transcriptionally, CBP and HDAC6 control Rel transcript levels by binding Rel regulatory regions and controlling histone acetylation. REL re-expression in mesenchymal-like TS cells induces a mesenchymal-epithelial transition. Importantly, REL forms a feedback loop, blocking HDAC6 expression and nuclear localization. Together, our work defines a developmental program coordinating phenotypic switching.

在正常发育和疾病状态下，上皮和间充质表型之间的表型转换需要协调的基因表达。滋养层干 (TS) 细胞在植入和胎盘形成过程中经历上皮间质转化 (EMT)。在这些过程中协调基因表达的机制知之甚少。我们之前已经证明 MAP3K4 调节的染色质修饰剂 CBP 和 HDAC6 在 TS 细胞中的 EMT 期间分别调节数千个基因。在这里，我们显示 CBP 和 HDAC6 协调仅 183 个基因的表达，这些基因被预测为表型转换的关键调节因子。排名最高的共调控基因是 NF-κB 家族成员Rel. 尽管 NF-κB 主要受转录后调控，但 CBP 和 HDAC6 通过结合Rel调控区和控制组蛋白乙酰化来控制 Rel 转录水平。间充质样 TS 细胞中的 REL 重新表达诱导间充质-上皮转化。重要的是，REL 形成一个反馈回路，阻止 HDAC6 表达和核定位。我们的工作共同定义了一个协调表型转换的发育程序。